Cortical dysfunction has been implicated in the pathophysiology of schizophrenia (SCZ). Decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD67), encoded by GAD1, is found in SCZ postmortem brain. We report evidence of distorted transmission of single nucleotide polymorphism (SNP) alleles in 2 independent SCZ family-based samples. In both, allelic association was gender dependent of the affected offspring and one sample was catechol-o-methyltransferase (COMT) genotype dependent. We observed evidence of statistical epistasis between SNPs in COMT and GAD1. This suggests that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopamine (DA) function. This study is the result of an in silico prediction and validity must be determined experimentally. Increased risk for complex illness genetically is depended upon many genes with subtle effects. The observation that an interaction with COMT adds biologic plausibility for risk genes shows the importance of epistatic effects in mediating the strength of genetic association in psychiatric disorders. Another study used 3 independent cohorts to test for epistasis between SNPs in COMT and polymorphisms in other SCZ risk genes. There is biologic plausibility of an impact of COMT on the risk profile of several SCZ risk genes. COMT impacts on the signal-to-noise of cortical function, a putatively critical parameter in the pathophysiology of SCZ. To the extent that other risk factors, genetic and environmental, also increase risk for SCZ by impacting on cortical development and function, these effects might be expected to be exaggerated by effects of COMT. For example, DA and glutaminergic systems are critical components responsible for PF signal-to-noise tuning in WM. Our recent fMRI studies of genetic variation in these systems examined the individual and combined effects of COMT and GRM3 on dissociable components of the WM network. We observed an epistatic interaction of these genes on the engagement of PFC during WM. The GRM3 genotype was associated with inefficient PF engagement and altered PF coupling on the background of COMT Val/Val. Conversely, COMT Met/Met mediated against the effect of GRM3 genotype. In another study we examined COMT enzyme activity and protein expression in 6 age groups of normal controls, from neonates to aged and found that COMT protein expression is related to Val158Met genotype and is elevated from neonates and adulthood. These increases may reflect changes in the PFC DA system and stresses the increasing importance of COMT for PFC dopamine regulation during maturation.[unreadable] [unreadable] As characterization of single genetic variants rapidly proceeds, the research turns to dissecting gene-gene and gene-environment interactions. In one study we examined DARPP-32 encoded by PPP1R1B. We identify a common PPP1R1B haplotype which predicts mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests and imaging revealed an impact on neostriatum, and functional connectivity of PFC. As we know, DA plays a critical role in hippocampal processing, which is implicated in emotion regulation. We examined genotype effect of COMT Val158Met on corticolimbic circuitry and functional connectivity during processing of salient stimuli and the relationship to novelty seeking. We found the Met allele associated with increases in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of negative faces. The ability of COMT Met/Met subjects to focus attention and inhibit interference may have deleterious effects in environments requiring rapid and flexible processing. Another gene-gene interaction is observed in the magnitude of Neuregulin1 (NRG1)-induced migration associated with SNPs in the NRG1 and COMT genes. The functional COMT Val/Met SNP does in fact influence NRG1-mediated cell migration. Val/Val subjects evinced significantly lower NRG1-mediated migration compared with Met/Met. If common genes shared by neuronal cells and lymphocytes regulate NRG1-induced migration, this suggest that NRG1-mediated neural migration may be abnormal in patients with SCZ during development. Although controversial, aberrant neuronal migration has been suspected from reports of cytoarchitectural abnormalities in patients with SCZ. Thus, our findings suggest a potential molecular pathway involved in the neurodevelopmental origins of SCZ.[unreadable] [unreadable] A wide-range of neuropsychological tests is typically necessary to identify cognitive deficits in SCZ and routinely measure multiple cognitive processes, with many tests leading to the problem of multiple comparisons. We looked at the feasibility of using factor analysis to reduce the number of variables and to better understand the cognitive architecture in SCZ. We identified factor parameters for SCZ, unaffected siblings, and control subjects, both separately and as a composite group. Analysis yielded a 7-factor model that included verbal memory, WM, visual memory, IQ/speed/fluency, executive function, attention and digit span. A factor structure representative of all the groups was identified and reduced to 7 variables of interests. These findings provide the first confirmation that cognitive structure is comparable in family members of SCZ patients, in patients and controls. The difference in cognition between affected individuals, siblings and controls is mainly in the level of performance on neuropsychological tests, not in the cognitive architecture underlying performance. This work serves as further proof of the concept that factor analysis can be useful in reducing the complexity of cognitive measures. Reducing variables will decrease redundant comparisons and increase replicability by reducing type 1 error due to multiple comparisons. This approach may lead to the development of improved pharmacological treatments, although more research is needed in order to understand whether specific cognitive domains are linked to separate abnormalities at the neurological level. [unreadable] [unreadable] Understanding the dynamics of DA function in the PFC and its role in PFC physiology has opened up avenues for new therapeutics when PFC function is compromised. The COMT Val158Met SNP predicts performance in PF executive function tasks and neurophysiological response. COMT Val/Val subjects perform less efficiently than Met/Met. These findings raise the possibility of new pharmacological interventions for the treatment of PFC dysfunction and of predicting outcome based on COMT genotype. One strategy may use COMT inhibitors, such as tolcapone. A second strategy increases DA concentrations. A third possibility involves Modafinil, a drug with positive effects on WM in rodents. The potential of these drugs to improve executive cognitive function by selectively increasing DA load in the frontal cortex but not in subcortical regions, and the possibility that response may relay on COMT, provides a novel genotype-based targeted pharmacological approach without abuse potential for the treatment of cognitive disorder in conditions involving PFC dysfunction. In a closer examination we performed a randomized, double blind, placebo controlled, and crossover design of Tolcapone in normal subjects stratified by COMT genotype. Enzyme activity was measured in peripheral blood. We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug effect by genotype interaction, such that COMT Val/Val improved, and Met/Met worsened. There was a significant tolcapone-induced improvement in efficiency of information processing in PFC during a WM test. We show enhancement of PF cortical function in normal human subjects with a non-stimulant drug having COMT inhibitory activity.